Several different methods of preparation of salts of 2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]ethanol (quetiapine) and their purification, e.g. of quetiapine hemifumarate in various crystalline modifications, have been described so far.
In the original patent EP 0 240 228, quetiapine hemifumarate is prepared from the quetiapine base, which has been previously purified by column chromatography. Thus purified base is mixed hot with fumaric acid in ethanol, giving a solution from which, after cooling, quetiapine hemifumarate is crystallized.
A similar method of preparation is described in patent application US 2006/0063927.
In another patent, U.S. Pat. No. 6,372,734, quetiapine hemifumarate is prepared from the crystallized quetiapine base, which is, under boiling, mixed with a solution of fumaric acid in a mixture ethanol/methanol. Crystallized quetiapine hemifumarate is isolated after being cooled to 0° C.
In US Pat. Appl. Publ. 2004/0220400, quetiapine hemifumarate is prepared by adding fumaric acid, after completion of the reaction, directly to the reaction solution which contains toluene, n-butanol, or dimethylformamide as the solvent. After isolation, crude quetiapine hemifumarate has to be purified by further crystallizations from alcohols. The yields range about 70% of the theory.
In US Pat. Appl. Publ. 2004/0242562, the purified quetiapine base is dissolved in a solvent selected from the group of ketones, esters, or ethers. Fumaric acid is then added, and after it dissolves, quetiapine hemifumarate is allowed to crystallize. The yields are about 85%. The product obtained is further purified by crystallizations.
According to international patent application WO 2004/078735, quetiapine base is dissolved in a solvent selected from the group of ketones or esters of formic or acetic acids. Fumaric acid is then added, and after it dissolves, quetiapine hemifumarate is allowed to crystallize.
International patent application WO 03/080065 describes, inter alia, purification of quetiapine hemifumarate by dissolving quetiapine hemifumarate in a mixture containing water, a lower alcohol, or a dipolar aprotic solvent. After it dissolves, it is allowed to crystallize spontaneously, or is precipitated with a suitable solvent.
According to international patent application WO 2006/027789, quetiapine hemifumarate is prepared by dissolving the quetiapine base in acetone and by subsequent action of fumaric acid.
Disadvantages of the aforementioned methods:                In most cases, pure quetiapine base (for example in the crystalline form) is used as the starting substance, which has to be isolated first and then dissolved again.        The obtaining of pure quetiapine base is demanding for energy and time, involving losses thereof and thermal exposition during concentrating the solutions, which leads to formation of impurities.        Another common disadvantage comprises the relatively high solubility of salts of quetiapine in the solvents in which crystallization proceeds, and losses during crystallization associated.        
To eliminate the aforementioned disadvantages, the authors of this invention have carried out extensive research with the following result. Numerous dependencies, unknown up to date, have been discovered during the preparation and purification of salts of quetiapine. It has been found out that the quetiapine base does not have to be purified either from side substances, or from residual solvents or water. The method according to the invention makes it possible to combine several steps and process the product without further isolating, drying, or purifying. Therefore, this method has a significant influence on the yields, the rate of processing, technological equipment, and hence also costs.
It has been found out that in forming the salt in a mixture of an aromatic hydrocarbon with ketones or esters in a suitable ratio the drawbacks of the methods in which these solvents are used separately are removed, namely toluene in case of US Pat. Appl Publ. 2004/0220400, and ketones or esters in US Pat. Appl. Publ. 2004/0242562. In the case of aromatic hydrocarbons, a sticky, difficult-to-isolate product is formed, and in the case of ketones or esters, it is necessary to remove the extraction solvent (mostly toluene), to isolate pure quetiapine base, and the yield of the formation of the salt is lower.